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Cellular Stress Leads to the Formation of Membraneless Stress Assemblies in Eukaryotic Cells Van Leeuwen, Wessel; Rabouille, Catherine

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Cellular Stress Leads to the Formation of Membraneless Stress Assemblies in Eukaryotic Cells Van Leeuwen, Wessel; Rabouille, Catherine University of Groningen Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells van Leeuwen, Wessel; Rabouille, Catherine Published in: Traffic DOI: 10.1111/tra.12669 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): van Leeuwen, W., & Rabouille, C. (2019). Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells. Traffic, 20(9), 623-638. https://doi.org/10.1111/tra.12669 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 27-09-2021 Received: 15 March 2019 Revised: 10 May 2019 Accepted: 30 May 2019 Uncorrected manuscript published: 1 June 2019 Published on: 30 July 2019 DOI: 10.1111/tra.12669 REVIEW Cellular stress leads to the formation of membraneless stress assemblies in eukaryotic cells Wessel van Leeuwen1 | Catherine Rabouille1,2 1Hubrecht Institute of the Royal Netherlands Academy of Arts and Sciences, and University Abstract Medical Center Utrecht, Utrecht, the In cells at steady state, two forms of cell compartmentalization coexist: membrane- Netherlands bound organelles and phase-separated membraneless organelles that are present in 2Department of Biomedical Science of Cells and Systems, University Medical Center both the nucleus and the cytoplasm. Strikingly, cellular stress is a strong inducer of the Groningen, Groningen, the Netherlands reversible membraneless compartments referred to as stress assemblies. Stress assem- Correspondence blies play key roles in survival during cell stress and in thriving of cells upon stress Catherine Rabouille, Hubrecht Institute of the relief. The two best studied stress assemblies are the RNA-based processing-bodies (P- Royal Netherlands Academy of Arts and Sciences & University Medical Center Utrecht, bodies) and stress granules that form in response to oxidative, endoplasmic reticu- Utrecht, the Netherlands. lum (ER), osmotic and nutrient stress as well as many others. Interestingly, P-bodies Email: [email protected] and stress granules are heterogeneous with respect to both the pathways that lead to Peer Review their formation and their protein and RNA content. Furthermore, in yeast and Dro- The peer review history for this article is available at https://publons.com/publon/10. sophila, nutrient stress also leads to the formation of many other types of prosurvival 1111/tra.12669/ cytoplasmic stress assemblies, such as metabolic enzymes foci, proteasome storage granules, EIF2B bodies, U-bodies and Sec bodies, some of which are not RNA-based. Nutrient stress leads to a drop in cytoplasmic pH, which combined with posttransla- tional modifications of granule contents, induces phase separation. KEYWORDS membraneless organelles, metabolic enzyme foci, nutrient stress, P-bodies, pH drop, prosurvival, Sec bodies, stress assemblies, stress granules 1 | INTRODUCTION: MEMBRANE-BOUND that are peripherally associated with the membrane. Together, these AND MEMBRANELESS ORGANELLES features define key aspects of organelle functional identity. The mem- COEXIST IN INTERPHASE CELLS brane defines the type of communication between membrane-bound organelles as well with the other parts of the cell, mediated by small Cells are highly compartmentalized to limit biochemical reactions in lipidic vesicle and tubule carriers as well as by membrane contact sites.1 space. A large component of cell compartmentalization is provided by Membrane-bound organelles, their biogenesis, their maintenance, how membrane-bound organelles (Figure 1), that is, organelles which are they function and communicate—collectively referred to as membrane surrounded by a sealed lipid bilayer. The membrane defines the traffic—have been extensively studied in the last four decades and has boundary of the organelle, separates the lumen from the surrounding yielded a Nobel Prize in Physiology and Medicine in 2013.2 cytoplasm, and limits the biochemical/enzymatic reactions that are The second type of stable cellular compartments are membraneless catalyzed by and within the organelle. Compartmentalization also organelles. Although first described nearly 200 years ago with the allows for interactions with a specific pool of cytoplasmic proteins observation of the nucleolus,3,4 membraneless organelles have recently This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2019 The Authors. Traffic published by John Wiley & Sons Ltd. Traffic. 2019;20:623–638. wileyonlinelibrary.com/journal/tra 623 624 VAN LEEUWEN AND RABOUILLE Plasma membrane FIGURE 1 Schematic of cell compartmentalization. Membrane-bound organelles are represented in black, the Peroxisome stable/basal membraneless organelles are Lysosome Endosome in blue. The green box presents the Mitochondria P-body formation of P-bodies and stress granules Nucleus upon many stresses, whereas the red box presents the stress assemblies formed Germ granule/ No P granule upon nutrient stress Paraspeckle Pyrenoid RNA PML granule body ERES ER microtubules Golgi Centrosome Cellular stress Nutrient stress (oxidative, ER stress) Sec body Proteasome storage enzyme granule filament Enlarged Stress granule P-body EIF2B body Stress granule Enlarged Enlarged U-body P-body (re-)gained the attention of bio-physicists for their unique mechanism expression of mutated proteins. For instance, expression of amyloids, of formation by phase separation and for their material properties.5 Like proteins with long poly-glutamine tracts (PolyQ proteins; see review24), membrane-bound organelles, membraneless organelles appear to sup- or mutated RNA-binding proteins such as FUS25 or HnRNPA126,27 can port specific biochemistries with critical functions in cellular homeosta- lead to the formation of irreversible membraneless compartments. Fur- sis and development. The differences and similarities in both types of thermore, the expression of the mutant form of C9Orf72 can modify cell compartmentalization have been described in 6 the dynamics of membraneless compartments and make them Membraneless organelles are present in both the nucleoplasm and the pathological.28 cytoplasm of most eukaryotes. Membraneless organelles in the nucleus Many reversible membraneless compartments are also strongly include the nucleolus, Cajal bodies, nuclear stress bodies, nuclear speckles, induced by cellular stress; we will refer to these as stress assemblies. interchromatin granule clusters, paraspeckles, Sam68 nuclear bodies, PML After consideration of the general principles driving the formation of oncogenic domains, transcription histone locus bodies and Oct1/ membraneless organelles in the first part of this review, we describe PTF/transcription domains (reviewed in References 5,7. Membraneless the formation of stress granules and enlarged P-bodies upon different organelles in the cytoplasm include the centrosome,5 processing-bodies types of stress and describe their high level of heterogeneity (P-bodies) that are involved in mRNA decay, translational repression, (Figure 2). In the last part of this review, we focus on cytoplasmic microRNA-induced RNA silencing and RNA storage (see below),8 posterior stress assemblies that are induced by nutrient stress (Figure 3), a phe- germ granules in Drosophila,9,10 P-granules in Caenorhabditis elegans11-13 nomenon that has mostly been described in yeast and Drosophila. and neuronal granules transporting-specific mRNAs,14-16 as well as the non-RNA-based Pyrenoid in photosynthetic organisms17-20 (Figure 1). 2 | AN OVERVIEW OF MECHANISMS Interestingly, although seemingly stable, most constitutive mem- DRIVING FORMATION OF MEMBRANELESS braneless organelles are regulated according to the phase of the cell ORGANELLES cycle.21 Indeed, it appears that the size and abundance of most membraneless organelles are reduced as the cell enters mitosis. Many 2.1 | Membraneless compartments are formed by components appear to become diffuse, as if to ensure optimal partitioning. phase separation This phenomenon is reminiscent of membrane-bound organelles that frag- ment at the onset of mitosis,22 as extensively studied for the Golgi.23 The general consensus in the field is that membraneless organelles are While membraneless compartments have important functions in formed by phase separation of their components from the surround- cell physiology, they can become pathological when formed upon the ing nucleo- or cytoplasm.29-32 Phase separation defines the behavior VAN LEEUWEN AND RABOUILLE 625 of a seemingly homogeneous solution
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